The goal of this P01 application is to develop novel therapies for the treatment of non insulin-dependent diabetes mellitus (NIDDM). We seek to team senior members for the Marjorie Touchstone Diabetes Center (Project 1, Unger and Project 2, Newgard) with colleagues from the Molecular Cardiology Center for Biomedical Inventions (Project 3, Johnston and Project 4, Kodadek) here at the University of Texas Southwestern Medical Center in Dallas (UTSWMC). These principal investigators will be complemented buy key co-investigators that will provide expertise in molecular biology (Mangelsdorf, Meidell), nuclear magnetic resonance (NMR) analysis of metabolism (Sherry, Jones), and physical methods for gene targeting (Grayburn). The proposal contains plans for basic biology research relating to the mechanics of hepatic, cardiovascular, and islet dysfunction in obesity and NIDDM (Projects 1 and 2). It also contains proposals for development of novel technologies for gene targeting, controlled regulation of gene expression by small molecules, and manipulation of protein/protein interactions (Projects 3 and 4). Several points of integration of the biology and technology development programs have been identified and will be exploited. The fundamental motivation for assembling a team of this type is that no comprehensive and complete therapy for NIDDM currently exists. Given the complexity of the disease and the alarming rise in its incidence towards epidemic proportions, a focused effort for creation of new therapeutic strategies is required. Integration of biological research with technology development as we are proposing here may allow achievement of this difficult goal.